NEWER ANTIARRHYTHMICS

Dr D Sunil Reddy

• Antiarrhythmic drug therapy has been limited by both incomplete efficacy and a substantial potential for cardiac and extracardiac toxicity.

• As a result, only a few new antiarrhythmic agents have successfully completed clinical development programs and reached routine clinical usage over the past 20 years

• The drug therapy for atrial arrhythmias is often limited by the drug’s simultaneous effects on the ventricles, which has led to efforts to identify ionic channel targets specific to or preferentially located in the atria

WILL DISCUSS …

• RANOLAZINE• VERNAKALANT• IVABRADINE• CELIVARONE• BUDIADARONE• TECADENOSON

RANOLAZINE• Ranolazine is a novel antianginal drug with multiple

ion channel blocking antiarrhythmic activity

• Ranolazine is an inactivated Na Ch blocker (blocks late Na current) and is considered a Class IB agent

• Ranolazine also has effects on the delayed rectifier current (I Kr) and prolongs APD at any given pacing cycle length, with corresponding QT prolongation .

• It also inhibit s ryanodine receptor channel (RyR2)

• Atria show more depolarized resting membrane potential than ventricular myocyte, the consequence is an increased fraction of inactivated Na channels at a given membrane potential

• Ranolazine produces a use-dependent depression of several Na channels which can be found in human atrial myocytes even at higher rates

• The principal mechanism underlying ranolazine’s antiarrhythmic actions is thought to be primarily via inhibition of late I Na in the ventricles, and via use-dependent inhibition of peak I Na and I Kr in the atria

• In MERLIN-TIMI 36 study, ranolazine was shown clinically to reduce arrhythmia episodes, including NSVT, on ambulatory cardiac monitoring in pts presenting with ACS and despite causing modest QT prolongation, ranolazine use was not a/w an increased risk of SCD compared with placebo

It has been used in the suppression of ectopic ventricular activity and

for the reduction in VT burden and prevention of shocks in ICD recipients

Kaliebe JW, Murdock DK. Suppression of nonsustained ventricular tachycardia with ranolazine: WMJ. 2009;108:373–5

Bunch TJ, Mahapatra S, Murdock D, et al.Ranolazine reduces ventricular tachycardia burden and ICD shocks in patients with drug-refractory ICD shocks. Pacing Clin Electrophysiol. 2011;34:1600–6

RANOLAZINE IN AF

• In a secondary analysis from the MERLIN-TIMI 36 trial, ranolazine treatment was associated with a 30% reduction in new onset AF (p=0.08) as well as a significant reductions of supraventricular tachyarrhythmias (p<0.001)

• Ranolazine in particular works synergistically with the Class III antiarrhythmic agents, most commonly with amiodarone and can be used as an add-on therapy in patients with recurrent VT events while on a Class III antiarrhythmic agent

RAFFAELLO TRIAL

• Comparison of the efficacy of 3 doses of Ranolazine (low, intermediate & high)

versus placebo, given for up to 16 weeks, in maintaining sinus rhythm after successful DC cardioversion in patients with non-permanent atrial fibrillation (AFib) • Ongoing trial , results not yet published

HARMONY STUDY• The purpose of this study is to evaluate whether

treatment with ranolazine or low dose dronedarone reduces atrial fibrillation burden (AFB) in subjects with paroxysmal atrial fibrillation (PAF)

• Whether combination therapy (ranolazine and low dose dronedarone) is superior to individual drug therapy in reducing AFB

VERNAKALANT• Vernakalant is an atrial-selective, multiple ion

channel blocker being investigated for use in AF

• Vernakalant is an atrial repolarization-delaying agent with its major target I Kur

• Vernakalant also blocks I to and INa, although there is little effect on I Kr or Iks

• As I kur is present in higher density in the atria, vernakalant is relatively atrial selective

• Vernakalant infusion dose-dependently prolongs atrial ERP but has no significant effect on ventricular ERP or QT intervalThe I Na inhibition is rate- and voltage-dependent.

• Vernakalant has, therefore, a much greater effect in fibrillating atria than in the ventricle and is less likely to be proarrhythmic

• Most common side effects are hypotension , dysgeusia, sneezing, paresthesias, nausea due to Na channel inhibition in CNS .

CLINICAL EFFICACY

TRIALS CONDUCTED SO FAR …• Conversion of Rapid Atrial Fibrillation Trial [CRAFT]• Atrial arrhythmia Conversion Trial [ACT]

ACT I , II , III , IV• AVRO

• Vernakalant was administered by a 10-minute infusion of 3 mg/kg F/B a 15-min observation period then a second 10-min infusion of 2 mg/kg if still in AF

VERNAKALANT FOR CONVERSION OF AF TO NSR

• The lack of an oral formulation for long-term therapy is an obvious limitation for the use of intravenous vernakalant

• Results of clinical trials showed that the efficacy of vernakalant decreases with the duration of AF

• The conversion rate was substantially lower in AF lasting 3 to 7 days than 3 to 48 hours

• Longer-duration AF (8 to 45 days) rarely responded to vernakalant

• Vernakalant appears less effective for acute conversion of AF in association with HF and the incidence of serious hypotension and ventricular arrhythmia is higher in this patient population

IVABRADINE• Ivabradine selectively inhibits the spontaneous

pacemaker activity of the sinus node by blocking the If current

• This reduces the heart rate without altering myocardial contractility or other hemodynamics

• Approved as a treatment for inappropriate sinus tachycardia

• The blockage of the If current is dose dependent and heart rate– dependent limiting the risks of symptomatic bradycardia

• Some remodeling of the sinus node appears to occur in response to ivabradine, but no rebound tachycardia has been seen after discontinuing it

• Electrophysiological studies of Ivabradine in humans have shown little effect on the conduction system or on atrial and ventricular refractoriness

• The oral bioavailability is approximately 40%

• It takes 60 to 90 minutes to reach maximal plasma concentrations. The half-life is approximately 2 hours

• In the BEAUTIFUL study there was no difference in the primary end point of CVD or admissions for acute infarction or heart failure

• In pts with BHR - 70 bpm, however, the secondary end points of admission for fatal and nonfatal MI and the need for revascularization were significantly reduced.

• Little trial data exists regarding the treatment of atrial tachyarrhythmias with ivabradine

• Most side effects are dose-related.

• Ion channels in the retina that generate the Ih current are also affected leading to phosgenes

CELIVARONE• It is a noniodinated benzofuran derivative with EP

effects similar to amiodarone and dronedarone

• Its efficacy at 300- or 600-mg daily doses for conversion of atrial fibrillation and flutter was studied (CORYFEE )

• Dose ranging study compared Celivarone at 50, 100,200, or 300 mg once daily with amiodarone for maintenance of sinus rhythm (MAIA) 

• There was no significant difference in the rate of spontaneous conversion to sinus rhythm between the treatment and control groups.

• Celivarone does not appear to be efficacious in the maintenance of sinus rhythm in AF/AFL patients or for the conversion of AF/AFL patients

Khitri AR et al; Celivarone for maintenance of sinus rhythm and conversion of atrial fibrillation/flutter;J Cardiovasc Electrophysiol. 2012 May;23(5):462-72

• Trials have shown the lowest rate of atrial fibrillation recurrence at 50 mg dose with no enhanced efficacy at the higher doses

• A 46% reduction in the number of sustained ventricular arrhythmia episodes requiring ICD therapy was noted in the 300 mg daily group, but this reduction was not statistically significant

Kowey PR, Aliot E, Cappucci A, Connolly SJ, Crijns H, Hohnloser SH,Kulakowski P, Roy D, Radzik D. Placebo-controlled double-blind dose ranging study of the efficacy and safety of celivarone for the prevention of ventricular arrhythmia-triggered ICD interventions.JAmColl Cardiol.2008;51:A2

BUDIODARONE• Unlike dronedarone, budiodarone , retains 2 iodine

atoms in its molecular structure • Budiodarone has electrophysiological properties

similar to amiodarone and has a shorter half-life than amiodarone

• Ester modification of the compound changes its metabolic pathways such that budiodarone undergoes rapid degradation by plasma and tissue esterases to an inactive compound

• There are as yet no published data on long-term exposure to budiodarone, so its potential for chronic toxicity is unknown

• In a study conducted in patients with paroxysmal AF and a previously implanted dual-chamber pacemaker , the percent change from baseline AT/AFB over 12 weeks of treatment compared to placebo was studied

• The median reduction of AT/AFB for the 400 and 600 mg BID groups vs. placebo was 54% and 74% (p = 0.01 and 0.001), respectively.

• The budiodarone dose-response was statistically significant (p < 0.001)

• Number and duration of AT/AF episodes were reduced

Ezekowitz MD A randomized trial of budiodarone in paroxysmal atrial fibrillation; J Interv Card Electrophysiol 2012 Jun;34(1):1-9

TECADENOSON

• Tecadenoson is a novel selective A1 adenosine receptor agonist that is currently being evaluated for the termination of SVT and rate control for atrial fibrillation

• It is associated with fewer adverse effects such as flushing, dyspnea, chest discomfort, and hypotension than adenosine

• Tecadenoson also appears to be associated with a lower incidence of atrial fibrillation following conversion of PSVT compared to adenosine (15%)

• It causes significant prolongation of AV nodal conduction and refractoriness without causing hypotension or negative inotropic effects

• It has a longer half-life than adenosine (20 to 30 minutes)

• TEMPEST trial was done to evaluate tecadenoson in the termination of SVT

• A multicenter,double-blinded, placebo-controlled trial that randomly assigned 181 pts to receive placebo vs one of several dose-escalating regimens of tecadenoson for termination of SVT.

• The conversion rates were 73.5% in the tecadenoson-treated pts and 6.7% in the placebo group.

• Rates of conversion did improve with dose escalation and the side effects were relatively mild and increased with dose escalation

FUTURE TARGETS FOR NOVEL ANTIARRHYTHMIC DRUGS

• Specific acetylcholine-regulated K current inhibition– Tertiapin

• Abnormal calcium handling– RyR2 modulation ( ? Ranolazine )– SERCa 2A modulation

• Gap junction modification– Rotigaptide

• Na/Ca exchanger inhibition– KBR-7943 and SEA-0400

• Stretch-induced or ischemia-induced ATP-sensitive K current inhibitors– HMR-1883, HMR-1098, HMR-1402, ?

Glibenclamide

• Gene and cellular therapy

THANK YOU

• Almokalant • Almokalant • Ibutilide • Trecitilide • Ambasilide • Melperone • Terikalant

• Azimilide • Meobentine • Nibentan • Cardiocylide • Pranolium • Clofilium• Chromanol

• Ranolazine • Dofetilide• Risotilide • Sematilide • Ersentilde • Tedisamil

(blocks Ito)

• Atrial-selectiv e I Na Modulation– Vernakalant– Ranolazine

– Restoring Abnormal Ca2+ Handl ing• Ranolazine

1. Atrial-selectiv e Ion-channel Modulation

1. Abnormal G ap Junction Conduction1. rot igapt ide2. danegapt ide

• Azimilide, a class III agent wit h bot h IKr- and I Ks -blocking propert ies

• ALI VE [ AzimiLide post -I nf arct surViv al Ev aluat ion - unpublished] t rial